JPH0151263B2 - - Google Patents

Abstract

The invention relates to vessel prostheses formed from a porous vascular prosthesis impregnated with diisocyanate crosslinked gelatin for sealing the pores.

Description

DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is to provide an impregnated material that is easy to manufacture, has good mechanical properties, is completely compact, harmless to the recipient organism and is easy to handle, especially during implantation. The goal is to create artificial blood vessels.

This problem is solved by artificial blood vessels characterized in that they are porous but occluded with cross-linked gelatin, the impregnated gelatin being cross-linked with diisocyanates.

Isocyanate is a reactive nucleophilic group in gelatin,
In particular, it also reacts with amino groups and hydroxyl groups,
Forms stable bonds and cross-linked products. Diisocyanate crosslinks, unlike aldehyde crosslinks, are irreversible; in the latter case there is an equilibrium state, so that the aldehyde is reformed and re-released. At the end of the reaction, no more isocyanate remains and is no longer reformed from the crosslinked product. Diisocyanate cross-linked gelatin forms a compact impregnation with good mechanical properties, and due to the porosity of the vascular graft, only a small amount of gelatin and cross-linking agent is required, yet complete occlusion is achieved. be done.

Crosslinking of biological materials with diisocyanates is already known. For example, German published patent 2-
No. 2734503 describes a method for making collagen sponges, in which a partially decomposed collagen paste or slurry is mixed with diisocyanate, shock frozen to a temperature of -10 to -30°C, kept at a temperature below 0°C, and washed. and then processed and then dried. This method results in a soft porous foam or sponge. German published patent 2
In the method described in No. 3020611, the Achilles tendon is swollen into fibers, the fibers are then cross-linked using hexamethylene diisocyanate emulsified in a saline solution, and the cross-linked fibers are then used to form, inter alia, knittable ( Knittable) system is manufactured. However, these methods are not relevant to the problem of the present invention.

A porous vascular graft may have a porosity of about 2000 cm ³ /min/cm ² . As a result of the impregnated coating of gelatin mixed with diisocyanates according to the invention, this porosity can be completely eliminated. The degradation of gelatin thus cross-linked in the body is slow, matching the rate at which new tissue grows into the porous body of the artificial blood vessel and ensures natural occlusion.

The porous body of this vascular graft has the general structure of a woven vascular graft; for example, the smooth warped fabric according to German Patent No. 2009349;
3878565, or a double velor artefact construction according to German Patent No. 2613575. However, the artifact may also be a porous, non-woven artifact; for example, the expanded polytetrafluoroethylene artifact described in GB 1506432. The pores are closed by a thin cross-linked gelatin film, which is coated with a thin cross-linked gelatin film in order to occlude the artificial structures bounding the pores. The film-like coating of the individual structural elements of the vascular graft, with the addition of a membrane, results in a complete filling of the porosity or an occlusion that differs from a complete coating. For example, in the case of textile prostheses, the individual fibers or fiber bundles or strands are coated with a cross-linked gelatin film, by means of which they are continuous across the spaces between the fibers or strands, ie at different planes within the wall of the graft. As a result of this microstructure, handling of the vascular graft is improved rather than impaired by impregnation.

Unlike collagen, which is a heterogeneous fibrous material and therefore cannot be completely compacted in a thin layer,
The fact that gelatin is a material that exists in the form of a homogeneous solution also allows for sufficient occlusion of the vascular graft using a small amount of impregnating material. The weight ratio of porous artifact to impregnated coating ranges from 1:0.2 to 1:3;
In particular, the ratio is about 1:1, with additional additives such as plasticizers optionally present in the impregnated coating. In order to prevent the impregnated coating from drying out and to improve its elasticity, hydrophilic plasticizers, in particular glycerol and other known polyols, are advantageously used. The moisture content of the impregnated coating in the dry state is preferably between 15 and 25% by weight, in particular between 17 and 22% by weight, based on the weight of the crosslinked impregnated coating.

A preferred crosslinking agent is hexamethylene diisocyanate. However, other diisocyanates,
It is also possible in particular to use aliphatic diisocyanates having 4 to 12, more preferably 6 to 10 C atoms. Compared to formamide, longer chain crosslinkers are more favorable for the elasticity of the product due to the so-called spacer function of the bridges between protein chains.

The impregnated coatings of the vascular grafts according to the invention contain therapeutically active materials or other active substances, as is known up to now. In a particularly preferred embodiment, the materials and active substances mentioned above are not merely incorporated into the impregnated coating, but instead are adhered to or encapsulated in a support or carrier and are released in delayed form. For this purpose, impregnated coatings,
In particular, gelatin contains components that absorb or adsorb active substances, which can then be released gradually. Particularly suitable components of this type are exchangers, especially ion exchangers. In a particularly preferred embodiment of the invention, at least a portion of the gelatin consists of succinylated gelatin having such properties.
As a result of their basic function, aminoglycosides such as gentamicin are well retained by such modified gelatins. Since modified gelatin does not gel as well as normal gelatin, the proportion of modified gelatin usually depends on the gelling ability of the mixture and is in the range of 10 to 50% by weight relative to the total amount of gelatin. Easily gelatinous gelatin such as edible gelatin is preferred (Bloom value 110
~300, preferably 240-280). When crosslinking with diisocyanates, the modified gelatin with exchanger function is also crosslinked, whereby the therapeutically active material or active substance is attached to the actual gelatin structure.

The method of the invention for producing an impregnated vascular graft is characterized in that a porous vascular graft is impregnated with an aqueous gelatin solution, the gelatin is gelled, then carefully dehydrated, in particular air-dried, and the pre-impregnated product formed is crosslinked with diisocyanates. It is said that

Diisocyanates not only react with gelatin, but also with other compounds with polar groups, such as water and alcohols, with the formation of undesirable by-products, such as insoluble urethane and urea derivatives. Impregnated coatings, as a result of their tightness, do not allow the elution of by-products formed within the coating - as is the case with known porous fibrous products cross-linked with diisocyanates - although diisocyanates are It was found that the tendency to form no harmful effects.

In order to impregnate the porous artificial blood vessel with the gelatin solution, it is preferable to immerse the artificial blood vessel in the solution. As a result of applying vacuum, the pores are completely filled with gelatin solution. The gelatin concentration of the solution can vary within a wide range and is preferably between 3 and 20, especially between 5 and 15% by weight of the impregnating solution. However, it is important that the solution is homogeneous. Impregnation is carried out at elevated temperatures, ie above 40° C., and gelling occurs by cooling. In an aqueous solution with a temperature of 60°C or higher, gelatin will decompose after being left for a long time, so the temperature should not be significantly higher than this. Therefore the temperature range is 45
-70°C, particularly preferably 55-60°C. The impregnating solution can contain plasticizers in an amount of up to 60% by weight, in particular from 10 to 40% by weight. Moisture content is usually 30
~97% by weight, more preferably 50-80% by weight. Depending on the gelling ability of the gelatin or gelatin mixture, the quantitative ratio of each other is such that the gelatin is soluble at the impregnation temperature and the impregnation solution is flowable, while about 20 to
Make sure that the gelatin gels when cooled to 30℃. During cooling, it is preferred to move the artifact impregnated with the gelatin solution to achieve a uniform coating thickness of gelled gelatin. For this purpose, after removing from the impregnation bath and letting the liquid drip for a short time,
Rotate the artifact around its long axis or cause it to undergo a tumbling motion.

It is important that the dehydration or drying of the gelled gelatin coating is carried out carefully to obtain an impregnated coating of good uniform structure. 25-35℃, especially about 30℃
It is suitable to air dry. The relative humidity of the drying air is preferably between 30 and 50%, particularly about 40%. Particularly if the artifact is immersed in a gelatin solution and a vacuum is subsequently applied, a single impregnation or treatment is sufficient to obtain complete densification, resulting in a small amount of material and favorable mechanical properties. With benefits.

The work is carried out using an excess of diisocyanate for gelatin crosslinking. This is firstly to achieve complete gelatin crosslinking and render it insoluble, and secondly in view of the expected secondary reactions. Preferably, the work is carried out without affecting the PH value. Gelatin can be kept at a normal pH value - usually around 5.5. Crosslinking reaction is 3.5
Performed in the PH range of ~7.5. Permissible reaction times of about 5 to 10 hours are reached during crosslinking at ambient temperature, in which case there are no detrimental secondary reactions and no special measures have to be taken.

To carry out the crosslinking reaction, the pre-dried gelatin-impregnated coating can be easily moistened.
Particularly suitable is the use of diisocyanate solutions in polar organic solvents. Solvents that are miscible with water and plasticizers are preferred; isopropanol is particularly suitable. The diisocyanate diffuses into the gelatin coating from the crosslinking solution and reacts with the gelatin with crosslinking. For this purpose it is convenient to immerse the artifact in a crosslinking solution. The operation is carried out in a significant excess of diisocyanate - 10% of the stoichiometry required for crosslinking.
The diisocyanate concentration in the crosslinking solution is preferably 3% by weight or less to maximize suppression of secondary reactions, although diisocyanate is also a component of the crosslinking solution. This is because they can react. Diisocyanate is 0.03 to 3% by weight, more preferably 0.05 to 0.5
% by weight, preferably about 0.1% by weight. Preferably, the crosslinking solution also contains a plasticizer and/or water to introduce the plasticizer and water into the gelatin coating or to prevent the water and/or plasticizer from escaping from the gelatin coating during the crosslinking reaction. . The concentration of plasticizers, especially glycerol, is between 0 and 60, especially between 10 and 60.
It is 20% by weight. In extreme cases the water content may go up to 70% by weight, but it is usually much lower, from 3 to 30, especially from 5 to 10% by weight. For preferred embodiments, it is important that the water content is very low so that the diisocyanate can be present in solution in the crosslinking solution. The relative movement between the crosslinking solution and the graft allows the diisocyanate concentration on the graft surface to be kept as high as possible. In a preferred embodiment, the crosslinking solution is constantly circulated or pumped and filtered at the same time. Insoluble by-products are continuously removed, so that deposits on the vascular graft and therefore contamination are avoided. Thanks to the low diisocyanate concentration, the crosslinking solution can be handled safely. Since the diisocyanate concentration is constantly decreasing during the crosslinking reaction, safe disposal is possible at the end of the reaction. However, variants are also possible, for example in which the operation is carried out at a substantially constant diisocyanate concentration.

In a particularly preferred embodiment of the invention, the water content and preferably the plasticizer content of the dehydrated, not yet crosslinked, but predried gelatin-impregnated coating is also the water content and - preferably the plasticizer content in the crosslinking solution. - and are adjusted so that when the pre-dried impregnated artificial blood vessel is immersed in the crosslinking solution, they are approximately in equilibrium with each other. This results in
Unfavorable concentration changes, which could lead, for example, to leaching or swelling of gelatin-impregnated coatings that have not yet been crosslinked, can be avoided.

At the end of crosslinking, the gelatin-impregnated coating is made waterproof, where it can be washed with water, optionally adding a plasticizer to it and then carefully drying. Preference is given to sterilization by irradiation, which is already known.

Other features and details of the invention can be gleaned from the following description of preferred embodiments in conjunction with the subclaims. The individual features can be realized alone or in combination.

Example 1 A knitted double microvelor vascular graft of pleated polyethylene terephthalate fibers was fixed to a frame and treated with 7.5% by weight gelatin and 15% as plasticizer.
It was soaked in an aqueous gelatin impregnation solution containing % by weight of glycerol in deionized water at a temperature of 60°C.

Place the gelatin solution under vacuum to completely remove any air trapped within the textile artifact. After the bubbles rise, the artifact is left in the solution under reduced pressure for about 15 minutes and then returned to normal pressure. Remove the artifact from the impregnation solution and drain briefly. Then let it cool to room temperature and at the same time make a light tumbling motion. After the coating material has gelled, the coated artifact is placed in a weathering chamber, with air therein having a relative humidity of 40%, at 30 °C, until the residual moisture content in the impregnating solution is approximately
Dry until 20%.

The pre-dried artifact is immersed in a crosslinking solution containing 0.1% by weight hexamethylene diisocyanate, 15% by weight glycerol, 8.5% by weight water and 76.4% by weight isopropanol. The coated artifact is left in this solution for 8 hours at ambient temperature, during which time the solution is constantly pumped and filtered. Once the crosslinking is complete, the artifact is removed from the crosslinking solution, washed with an aqueous solution of 15% glycerol, carefully dried again at 30°C and 40% relative humidity, and then dried at 15% on the basis of the impregnated coating.
Bring to ~20% residual moisture content. The artifact is then cut to the nominal length, packed individually, and sterilized by irradiation.

Artifacts impregnated in this way are completely dense. The impregnated coating is within the fibrous structure of the fabric,
It is almost invisible to the naked eye. The artifact exhibits a bright-colored appearance and is flexible, capable of being compressed and stretched axially. After implantation of the prosthesis, the crosslinked coating material is absorbed at the same rate as the natural tissue subsequently grows, without the degradation products exhibiting any harmful effects. Impregnated coatings are also immunologically and toxicologically acceptable.

Example 2 The method of the example is repeated, except that instead of the edible gelatin, a mixture of 70% by weight edible gelatin and 30% by weight succinylated gelatin is used. The crosslinked impregnated coating obtained in this way contains additional acid groups,
These acid groups make the impregnated coating suitable for storage, for example by diffusion and binding of therapeutically active substances with basic properties. These therapeutically active substances are released very slowly after implantation of the prosthesis, so that, for example, infection protection is achieved over a long period of time.

Example 3 A pleated, double-velor knit artificial blood vessel made of polyethylene terephthalate fibers is fixed to a frame as in Example 1 and then impregnated with gelatin by the dipping method. The aqueous impregnating solution contains 10% gelatin and 20% glycerol and has a temperature of 60%
It is ℃. As in Example 1, the textile artifact is placed under vacuum and thoroughly vented. Remove the artifact, drain briefly, and gently tumble the frame while the impregnating solution gels. After separation of the coating, the impregnated artifact is transferred to a weathering chamber and carefully intermediate-dried, as in Example 1, until the residual moisture content of the impregnated coating is approximately 25%. The pre-dried artifact, clamped in a frame, is placed in a crosslinking bath containing 0.2% by weight hexamethylene diisocyanate, 50% by weight glycerol, 43.3% by weight isopropanol and 6.5% by weight water. As in Example 1, the coated artifact is left in the crosslinking solution at ambient temperature for 8 hours. The subsequent washing is carried out as follows: the clamped artifact is exposed to a 30% aqueous glycerol solution for about 5 minutes in a circulatory manner at ambient temperature. After drying the impregnated coating of the artifact thus produced, the residual moisture content is approx.
It is 22%.

The coated artifact according to Example 1 contains 9.5% water 22% glycerol 18% crosslinked gelatin , 49.5% impregnated coating and 50.5% porous base body.

The artifact according to Example 3 consists of a porous artifact of 13% water, 32% glycerol , 16% crosslinked gelatin, or 61% impregnated coating, and 39% nits, by weight.

Based on the total weight of the impregnated coating, the latter is generally 10-30% water by weight 10-60% by weight plasticizer and 20-60% cross-linked gelatin by weight including.

Claims (1)

Claims: 1. An artificial blood vessel which is itself porous and is occluded by impregnation with cross-linked gelatin, the gelatin being cross-linked with diisocyanate. 2. The artificial blood vessel according to claim 1, wherein the artificial blood vessel structure bounding the hole is covered with a thin film of cross-linked gelatin, and the hole is closed with a gelatin membrane. 3. Vascular prosthesis according to one of the preceding claims, in which at least one therapeutically active material is inserted into the impregnated coating, which is preferably inserted in a depot manner to exhibit a delayed effect. 4. Artificial blood vessel according to claim 3, in which the impregnated coating, in particular gelatin, contains constituents with exchanger properties, in particular ion exchanger properties. 5. Method for manufacturing an impregnated vascular graft, in which a porous vascular graft is impregnated with an aqueous gelatin solution, the gelatin is gelled, the gelatin is then carefully partially dehydrated, in particular air-dried, and the resulting impregnated coating is subsequently crosslinked with diisocyanate. . 6. The method according to claim 5, wherein the impregnation of the porous artificial blood vessel with gelatin solution is carried out by immersion, in particular under vacuum. 7. One of claims 5 to 6, wherein a diisocyanate solution in an organic solvent is used for crosslinking the gelatin-impregnated coating, the organic solvent being preferably miscible with water and optionally added plasticizers. The method described in. 8 To crosslink the gelatin-impregnated coating, 0.03
It consists of ~3% by weight diisocyanate, especially hexamethylene diisocyanate, 0-60% by weight plasticizer, especially glycerol, 30-95% by weight solvent, especially isopropanol and 5-70% by weight water, in quantitative proportions with the diisocyanate in solution. 8. Process according to one of claims 5 to 7, using solutions that are mutually conditioned so as to be present.